4-aminoquinazoline cardiac stimulants

ABSTRACT

6,7-Dialkoxy-4-aminoquinazoline cardiac stimulants and synthetic methods for the preparation thereof.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to therapeutic agents and, in particular, tonovel 4-aminoquinazoline derivatives useful as cardiac stimulants.

2. Description of the Prior Art

Quinazolines are a well-known class of organic compounds, some of whichare reported to have useful therapeutic properties. U.S. Pat. No.3,517,005 discloses 4-aminoquinazoline derivatives with hypotensive andbronchodilator activity, and U.S. Pat. No. 3,511,836 reports hypotensiveactivity for 2,4-diaminoquinazolines. Scarborough et al., J. Org. Chem.,27,957 (1961) reports the preparation of several 4-(1-substituted3-pyrrolidinylmethylamino)quinazolines. Belgium Patent 811,856 teachesthe use of 4-(N-heterocyclicalkylamino)quinazolines as cardiacstimulants.

SUMMARY OF THE INVENTION

It has now been found that certain 6,7-dialkoxy-4-aminoquinazolines andtheir pharmaceutically acceptable acid addition salts are outstandinglyactive as cardiac stimulants.

A preferred group of compounds and their pharmaceutically acceptableacid addition salts are of the formula ##STR1## wherein R₁ is hydrogenor alkyl of one to three carbon atoms; R₂ is alkoxy of one to two carbonatoms; X is --CH=CH--, --CH₂ CH=CH-- or alkylene of one to three carbonatoms; and Y is a 3- or 4-substituent in ring C from the group --Z₁COR₃, --N(R₄)SO₂ R₅, --Z₂ CONR₆ R₇ or --Z₂ CSNR₆ R₇ wherein Z₁ is --CH₂--or --N(R₄)--; R₃ is alkyl of one to four carbon atoms, alkoxy of oneto four carbon atoms, benzyoxy, phenoxy, ethoxycarbonylmethyl orpyridyl; R₅ is alkyl of one to four carbon atoms, pyridyl or --NR₆ R₇ ;Z₂ is --O--, --CH₂ -- or --N(R₄)-- wherein R₄ is hydrogen, pyridyl,phenyl, alkyl of one to four carbon atoms or substituted said alkylwherein the substituent is amino, dimethylamino, hydroxy, pyridyl orphenyl; and R₆ and R₇ when considered separately are hydrogen or alkylof one to four carbon atoms and R₆ and R₇ when considered together withthe nitrogen to which they are attached form a piperidine ring, with theproviso that when X is --CH=CH-- or --CH₂ CH=CH-- Y is --CH₂ COR₃, CH₂COR₃, CH₂ CONR₆ R₇ or --CH₂ CSNR₆ R₇.

A class of especially preferred compounds are those wherein R₁ ishydrogen, R₂ is methoxy, X is --CH₂ CH₂ -- and Y is a substituent at the4-position of ring C.

Within this especially preferred class is a preferred group wherein Y isZ₁ COR₃ wherein Z₁ is --N(R₄)-- wherein R₄ is hydrogen or alkyl of oneto four carbon atoms and R₃ is alkyl or alkoxy each of one to fourcarbon atoms.

A second group within the especially preferred class are those wherein Yis --N(R₄)SO₂ R₅ wherein R₄ is hydrogen or alkyl of one to four carbonatoms and R₅ is pyridyl or --NR₆ R₇ wherein R₆ and R₇ when consideredseparately are hydrogen or alkyl of one to four carbon atoms and R₆ andR₇ when taken together with nitrogen to which they are attached form apiperidine ring.

A final group of compounds within the especially preferred class arethose wherein Y is Z₂ CONR₆ R₇ wherein Z₂ --O-- or --N(R₄ 0-- wherein R₆and R₇ when considered separately are each hydrogen or alkyl of one tofour carbon atoms, and R⁴ is hydrogen, alkyl of 1to 4 carbon atoms orpyridyl-substituted said alkyl.

In a broader sense this invention is meant to include within its scopecompounds of the formula ##STR2## wherein R₁ is hydrogen or a loweralkyl group; (R₂)_(n) represents 1to 3 optional substituents, each R₂being hydrogen, hydroxy or lower alkoxy, n being 1 to 3, or any two ofthe R₂ constitute a methylenedioxy or ethylenedioxy group attached toadjacent positions of ring A;

X represents --(CH₂)_(p) wherein p is 1 to 3, --CH=CH-- or --CH₂CH=CH--;

Y is attached to the 3- or 4-position of ring C and represents either:

a. a group of the formula --Z₁ COR₃ wherein Z₁ is --CH₂ --or --N(R₄)--,

R₃ is lower alkyl group optionally substituted by an amino, hydroxy,lower alkoxy, aryl or heteroryl group; a lower alkenyl-or loweralkynylmethyl group; a lower alkoxy group optionally substituted by anamino, aryl, heteroaryl, lower alkoxy or hydroxyl group; an aryl group;an aryloxy group; or a heteroaryl group; and

R₄ is a hydrogen atom; a lower alkyl group optionally substituted by anamino, lower alkoxy, hydroxy, carbethoxy, aryl or heteroaryl group; alower alkenyl-or lower alkynylmethyl group; an aryl group or aheteroaryl group;

b. a group of the formula --N(R₄)SO₂ R₅ wherein R₅ is defined as R₃ oris a group of the formula --NR₆ R₇ which R₇ is a hydrogen or a loweralkyl group and R₆ is defined as R₄, or R₆ and R₇ taken together withthe nitrogen to which they are attached form a saturated monocyclicheterocyclic ring; or

c. a group of the formula ##STR3## or --Z₂ CSNR₆ R₇

wherein Z₂ is Z₁ or --O--, and R₆ and R₇ are as defined provided thatwhen Z₂ is --N(R₄)--, R₄ and R₇ taken together may represent --(CH₂)₂--, --(CH₂)₃ -- or an o - phenylenediamine group; and R is a hydrogenatom or a lower alkyl group attached to the same carbon atom as Y;provided that when X is --CH=CH-- or --CH₂ --CH=CH--, R is absent and Yis --CH₂ COR₃, --CH₂ CONR₆ R₇ or --CH₂ CSNR₆ R₇ wherein R₃, R₆ and R₇are as defined above, Y being attached to an unsaturated ring carbonatom; and their pharmaceutically acceptable acid addition salts.

The term "lower" applied an aklyl, alkenyl, alkynyl or alkoxy groupindicates that such a group contains up to six carbon atoms, and suchgroup may be straight or branched chain. "Aryl" and "heteroaryl" as usedherein include unsaturated aryl and heteroaryl groups, and aryl andheteroaryl groups substituted by lower alkyl, lower alkoxy, hydroxy,halogen or acetamido groups.

By the term "amino" as used herein, is meant a group of the formula--NR₈ R₉ wherein R₈ is hydrogen or lower alkyl, and R₉ is hydrogen,lower alkyl, or aryl substituted lower alkyl, or R₈ R₉ taken togetherwith the nitrogen atom to which they are attached form a saturatedmonocyclic heterocyclic group. "Halogen" means fluorine, chlorine,bromine or iodine.

Compounds of the claimed invention containing one or more asymmetriccentres will exist as one or more pairs of enantiomers, and such pairsor individual isomers may be separable by physical methods, e.g. byfractional crystallization or chromatography of the free bases orsuitable salts. The invention includes the separated pairs as well asmixtures thereof, as racemic mixtures or as separated D- andL-optically-active isomeric forms.

It should also be understood that compounds of the present invention inwhich ring C is unsaturated may exist in tautomeric forms: ##STR4##

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention may be prepared by a number ofroutes:

Route A

Compounds of the formula (I) may be prepared by reacting anappropriately substituted quinazoline of the formula: ##STR5## whereinQ₁ represents a leaving group such as chloro-, bromo-, iodo-, loweralkoxy or (lower alkyl) thio, with an amine of the formula: ##STR6##with resultant elimination of HQ₁. Q₁ is preferably chloro or bromo. Thereaction is preferably carried out in an inert organic solvent such asethanol or dimethylformamide with heating, e.g. under reflux, in atemperature range of 75° to 150° C. for one or more hours, generally 1to 8 hours. When Q₁ is chloro-, bromo-, or iodo, the presence of a basesuch as triethylamine or of excess reagent of the formula (III) isadvantageous.

Any substituent groups in the reactants capable of displacing theleaving group Q₁, other than the ##STR7## of the compound of the formula(III), i.e. hydroxy, primary amino and secondary amino groups, shouldgenerally be protected prior to the reaction by conventional methods,the protecting groups being removed after the reaction by standardprocedures. Any hydroxy groups present may, if necessary, be protectedby, for example, abenzyl group, which group may be removed after thereaction by hydrogenolysis. Any primary or secondary amino groups may,if necessary, be protected by, e.g. a benzyl or t-butoxy carbonyl group,which groups can be removed after the reaction by, respectively,hydrogenation or mild acid hydrolysis.

The product is typically isolated and purified by evaporation of thesolvent in vacuo, followed by basification of the residue with a basesuch as aqueous sodium carbonate and extraction of the product into asuitable organic solvent, e.g. chloroform. After evaporation of theorganic solvent, the crude product is left as a residue which is eitherconverted to a salt and subsequently purified or recrystallized as thefree base.

Route B

Compounds of the formula (I) in which X is --(CH₂)p-13 and Y is --NR₄CONHR₆ or --NR₄ CSNHR₆ may be prepared by reacting a quinazoline of theformula: ##STR8## in which X is --(CH₂)p--, with either an isocyanate R₆NCO or isothiocyanate R₆ NCS, R₆ being other than hydrogen, or, toprepare compounds wherein R₆ is H, sodium or potassium cyanate orthiocyanate in the presence of acid. To prepare compounds in which R₆ isother than hydrogen, the reaction is preferably carried out by allowingthe reactants to stand together at room temperature for up to about 3hours in an inert organic solvent such as chloroform. The product maythen be isolated by evaporation of the solvent, and recrystallization ofthe thus-produced residue from a suitable solvent by normal methods.Alertnatively, the residue may be reacted with an acid to form a salt,and subsequently purified as such. To prepare compounds in which R₆ ishydrogen, the reactants are preferably heated together under reflux in asuitable solvent, e.g. aqueous ethanol, and in the presence of acid. Theacid may be supplied by using and acid addition salt of the compound ofthe formula (IV) as the starting material.

Any groups capable of reacting with isocyanate or isothiocyanate groupsor, as appropriate, with the cyanate or thiocyanate, other than ofcourse the --NH-- group of --NHR₄ in ring C, should generally beprotected by conventional protecting groups prior to the reaction, theprotecting group being removed by standard procedures after thereaction. Groups which it may be necessary to protect include hydroxy,primary amino and secondary amino groups, which groups may be present inR₂, R₄ and R₆.

Route C

Compounds of the formula (I) wherein X is '(CH₂)p-13 and Y is either--NR₄ COR₃, --NR₄ SO₂ R₅ or --NR₄ CONR₆ R₇, may be prepared by reactinga compound of the formula (IV) as previously defined with, asappropriate, either:

a. a haloformate or acyl halide of the formula Q₂ COR₃ wherein Q₂ ischloro or bromo;

b. a halosulfonate, sulfonyl halide or sulfamyl halide of the formula Q₂SO₂ R₅, Q₂ being chloro or bromo;

c. a carbamyl halide of the formula R₆ R₇ NCOQ₂ wherein R₆ and R₇ areboth other than hydrogen, and Q₂ is chloro or bromo;

or,

d. an anhydride or pyrocarbonate of the formula (R₃ CO)₂ O.

Preferably the reactants are allowed to stand together at roomtemperature for a period of up to a few hours in an inert organicsolvent, e.g. chloroform, in the presence of a base such astriethylamine.

Any groups in R₂ to R₇ capable of reacting with, or displacing asappropriate, the anhydride, pyrocarbonate or the group Q₂, e.g. hydroxy,primary amino, and secondary amino groups, should, if necessary, beprotected prior to the reaction by conventional protecting groups whichmay be removed after the reaction by standard procedures.

The product is typically isolated and purified by the method describedunder Route A.

Route D

Compounds of the formula (I) wherein X is --(CH₂)_(p) -- and Y is--OCONHR₆ or --OCSNHR₆ may be prepared by reacting a quinazoline of theformula: ##STR9## X being --(CH₂)_(p) --, with an isocyanate R₆ NCO orisothiocyanate R₆ NCS, R₆ being other than hydrogen, or, to preparecompounds in which R₆ is hydrogen, sodium or potassium cyanate orthiocyanate in the presence of acid. Generally the reactants are heatedtogether at temperatures of about 100° to 200° C in e.g. a stainlesssteel bomb for a period of about 24 to 48 hours in an inert organicsolvent.

Any groups capable of reacting with isocyanate or isothiocyanate groups,or, as appropriate, with the cyanate or isocyanate, other than ofcourse, the --OH group of ring C, should, if necessary, by protectedprior to reaction e.g. in the same manner as that described under RouteB. Similarly, the final product may typically be isolated by the methoddescribed under Route B.

Route E

Compounds of the formula (I) wherein X is --(CH₂)_(p) -- and Y is--NHCONR₆ -- R₇ or --NHCSNR₆ R₇ may be prepared by initially reacting aquinazoline of the formula: ##STR10## X being --(CH₂)_(p) --, withphosgene COC1₂ or thiophosgene CSC1₂ in the presence of a base, e.g.triethylamine, and in the presence of an inert organic solvent such aschloroform or toluene, the --NH₂ group in ring C being converted to an--NCO or --NCS group. Generally strong stirring of the reaction mixtureat room temperature is necessary, after which the mixture is allowed tostand for a few hours. A compound of the formula R₆ R₇ NH is then addedto the reaction mixture to react with the --NCO or --NCS group, theresulting mixture generally being allowed to stand for a few hours atroom temperature to complete the reaction. If desired, the intermediate--NCO or --NCS-containing quinazoline may be isolated and optionallypurified before reaction with the compound R₆ R₇ NH.

Any hydroxy groups, primary amino groups (other than, of course, the--NH₂ group of ring C), and secondary amino groups, should, ifnecessary, be protected by conventional protecting groups prior to thereaction, the groups being removed by standard procedures after thereaction.

The product may typically be isolated and purified by the proceduredescribed under Route A.

Route F

Compounds of the formula (I) in which X is --(CH₂)_(p) -- and Y is --NR₄-- COR₃, R₃ being other than lower alkoxy, substituted lower alkoxy andaryloxy, may be prepared by reacting a quinazoline of the formula (V) aspreviously defined with an ester of N-hydroxy succinimide of theformula: ##STR11## in which R₃ is other than lower alkoxy, substitutedalkoxy and aryloxy. The reaction is generally carried out by stirringthe reactants together at room temperature in an inert organic solvent,e.g. dry chloroform, for a few hours.

Any hydroxy groups or primary or secondary amino groups in R₂ to R₄should, if necessary, be protected prior to the reaction by conventionalprotecting groups which may be removed after the reaction by standardprocedures.

The product may generally be isolated by the method described underRoute A.

Route G

All compounds of the formula (I) wherein Y is --CH₂ CONR₆ R₇ may beprepared by reacting a compound of the formula: ##STR12## wherein Q₃ isa leaving group, such as a lower alkoxy, chloro-, or bromo-group, with acompound R₆ R₇ NH. The reactants are generally heated together neat,i.e. in the absence of any additional solvent, preferably in a closedstainless steel bomb at about 50° to 200° C for up to 48 hours. Heatingmay however not be necessary when Q₃ is a leaving group such as chloroor bromo. An inert organic solvent may however be added if required, andthe presence of a base such as triethylamine or excess reagent R₆ R₇ NHis advantageous when Q₃ is chloro or bromo.

Any substituent groups in R₂, R₆ and R₇ capable of reacting with thegroup --CH₂ CO Q₃, e.g. primary or secondary amino groups, should, ifnecessary, be protected prior to reaction and de-protected afterreaction.

The product is typically isolated and purified by the method describedunder Route A.

Route H

Compounds of the formula (I) in which X is --(CH₂)_(p) -- and Y is --NR₄COR₃, R₃ being a lower alkyl group substituted by an amino group (ashereinbefore defined), may be prepared by reacting a quinazoline of theformula: ##STR13## X being --(CH₂)_(p) -- and Q₄ being lower alkylsubstituted by chloro- or bromo-, with a compound of the formula R₈ R₉NH. Generally the reaction is carried out at room temperature in aninert organic solvent, e.g. chloroform, in the presence of a base suchas triethylamine or excess compound R₈ R₉ NH, for a period of a fewhours.

Any substituent groups in R₂ and R₄ capable of displacing the group Q₄,e.g. hydroxy and primary and secondary amino groups, should, ifnecessary, be protected prior to the reaction and de-protected afterreaction.

The product is typically isolated and purified by the method describedunder Route A.

Route I

Compounds of the formula (I) wherein ring C is unsaturated and Y is thus--CH₂ COR₃, --CH₂ CONR₆ R₇ or --CH₂ CSNR₆ R₇ may be prepared by reactinga quinazoline of the formula: ##STR14## wherein X is --(CH₂)₂ -- or--(CH₂)₃ --, with a phosphonate of the formula: ##STR15## wherein Y is--CH₂ COR₃, --CH₂ CONR₆ R₇ or --CH₂ CSNR₆ R₇. Generally the reaction iscarried out at moderate temperatures for a period of up to a few hours,and in an inert organic solvent such as dimethoxyethane in the presenceof a base, e.g. sodium hydride.

The product may be purified by the purification procedure describedunder Route B, and may be a mixture of tautomers.

Route J

All the compounds of the formula (I) in which Y is --CH₂ CONR₆ R₇ may beprepared by initially reacting a quinazoline of the formula: ##STR16##with a dehydrating agent such as di cyclohexylcarbodiimide, andN-hydroxy succinimide, to form an "activated" ester containing thegrouping: ##STR17## Preferably this reaction is carried out by allowingthe reactants to stand together for a few hours at room temperature inan inert organic solvent, e.g. chloroform. A compound of the formula R₆R₇ NH is then added to the mixture to obtain the desired product, themixture again generally being allowed to stand at room temperature for afew hours to complete the reaction. The reaction mixture is thenfiltered and the product recovered from the filtrate preferably via theisolation procedure described under Route B.

Any substituent groups in R₂ and R₆ capable of reacting with the --CH₂COOH or activated ester group, e.g. primary and secondary amino groups,should, if necessary, be protected prior to the reaction andde-protected after reaction.

Acid addition salts of the compounds of formula (I) may be prepared fromthe crude or pure free base product by the conventional technique ofreacting the free base with the acid in an inert solvent, e.g. by mixingalcoholic solutions of each and collecting the resulting precipitate byfiltration. The product may then be recrystallized to purity.

In the above methods due regard should be had to the possibility thatcarbethoxy-substituted lower alkyl groups may be attacked by primary andsecondary amino groups, and this should be borne in mind when preparingcompounds in which R₄ or R₆ contain a carbethoxy group.

The 4-substituted quinazolines used as starting materials in theprevious routes are either known compounds or are obtainable byanalogous procedures to those of the prior art, such as British PatentSpecification No. 1,199,768, or to those described in thisspecification. For example, the preparation of a compound of the formulaIV from a ketone starting material of the formula X is described in partA of Example 10, and many other compounds of the formula IV areanalogously obtainable. Furthermore, the preparation of a ketonestarting material for this route is exemplified in part A of Example 91and other such ketones are analogously obtainable. A route to thepreparation of an amine of the formula VI is described in part A ofExample 44, and other amines falling within this formula are analogouslyobtainable. An alternative route to the production of the amines of theformula VI could be via the catalytic hydrogenation of the correspondingcompounds of the formula IV in which R₄ is a benzyl group. Also, many ofthe compounds of the formula VIII are obtainable via Route A describedherein or analogously (Example 5 describes the preparation of a compoundof the formula VIII wherein the "leaving group" Q₃ is an ethoxy group).Similarly, starting materials of the formula IX can generally beobtained analogously to Route C as described herein. Starting materialsof the formula XI, which materials have a --CH₂ COOH group, aregenerally obtainable by hydrolysis of the corresponding ester, e.g.--CH₂ COOEt, the ester being obtainable via Route I described hereinwhen ring C is unsaturated, or via Route A when ring C is saturated.

As has been previously noted, compounds of the instant invention canform acid addition salts by virtue of the amino group. Basic compoundsof the present invention are converted to the acid addition salts byinteraction of the base with an acid either in an aqueous or non-aqueousmedium. In a similar manner, treatment of the acid addition salts withan aqueous base solution, e.g., alkali metal hydroxides, alkali metalcarbonates, and alkali metal bicarbonates to a basic pH or with a metalcation which forms an insoluble precipitate with the acid anion, resultsin a regeneration of the free base form. Such conversions are bestcarried out as rapidly as possible and under temperature conditions andmethod dictated by the stability of said basic products. The bases thusregenerated may be reconverted to the same or a different acid additionsalt.

In the utilization of the chemotherapeutic activity of those compoundsof the present invention which form acid addition salts, it ispreferred, of course, to use pharmaceutically acceptable salts. Althoughwater-insolutility, high toxicity, or lack of crystalline nature maymake some particular salt species unsuitable or less desirable for useas such in a given pharmaceutical application, the water-insoluble ortoxic salts can be converted to the corresponding pharmaceuticallyacceptable bases by decomposition of the salt as described above, oralternately they can be converted to any desired pharmaceuticallyacceptable acid addition salt.

Examples of acids which provide pharmaceutically acceptable anions arehydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, or sulfurous,phosphoric, acetic, lactic, citric, tartaric, succinic, maleic andgluconic.

The cardiac stimulant activity of the compounds of the invention isshown by their effectiveness in one or more of the following tests whichhave an excellent correlation with extrapilation to the effects in man:(a) increasing the force of contraction in the isolated, spontaneouslybeating, guinea pig double atria preparation; (b) increasing myocardialcontractility (left ventricular dP/_(dt) max.) in the anesthetised dogwith an implanted left ventricular catheter; (c) increasing myocardialcontractility in the conscious dog with an implanted left ventriculartransducer.

In test (a) the positive inotropic and chronotropic responses of theatria to the test compound are measured at several doses and comparedwith the responses elicited by isoprenaline. The comparison of the doseresponse curves obtained gives a measure of the force versus rateselectivity of the test compound.

In test (b) the positive inotropic action of the test compound followingintravenous administration is measured in the anaesthetised dog andcompared with that of isoprenaline. The potency of the inotropic action,the selectivity for increase in force versus frequency of contraction,and the duration of action of the positive inotropic effect of the testcompound are obtained, as are its peripheral effects, e.g. the effect onthe blood pressure.

In test (c) the positive inotropic action of the test compound followingintravenous or oral administration to a conscious dog with an implantedleft ventricular transducer is measured and compared with that ofisoprenaline. The potency of the inotropic action, the selectivity forincrease in force versus frequency of contraction, and the duration ofaction of the inotropic effect of the test compound are all obtained.

By virtue of the performance of the compounds of the invention in theabove tests, the preferred compounds have been found to be as follows:##STR18## wherein Y is: (a) --NHCONH(CH₂)₃ CH₃, i.e.,4-(4-{3-n-butyl-ureido}-piperidino)-6,7-dimethoxyquinazoline,

(b) --N(CH₃).CONH(CH₂)₂ CH₃, i.e.,4-[4-1-methyl-3-n-propyl-ureido}-piperidino]-6,7-dimethoxyquinazoline

(c) --NHCOOCH₂ CH₃, i.e.,4-[4-{ethoxycarbonylamino}piperidino]-6,7-dimethoxyquinazoline

(d) --O.CONHCH₂ CH₃, i.e.,4-[4-{ethylcarbamoyloxy}piperidino]-6,7-dimethoxyquinazoline

(e) --N(CH₃).SO₂ NH(CH₂)₂ CH₃, i.e.,4-[4-{N-methyl-N-(n-propylsulfamoyl)-amino}piperidino]-6,7-dimethoxyquinazoline

(f) --N(CH₃).COOCH₂ CH₃, i.e.,4-[4-{N-methyl-N-ethoxycarbonylamino}-piperidino]-6,7-dimethoxyquinazoline

(g) --NHCOOCH₂ CH(CH₃)₂, i.e.,4-[4-{iso-butoxycarbonylamino}piperidino]-6,7-dimethoxyquinazoline

(h) --NHCOO(CH₂)₂ CH₃, i.e.,4-[4-{n-propoxycarbonylamino}piperidino]-6,7-dimethoxyquinazoline

(i) --N(Et).COOEt, i.e.,4-[4{N-ethyl-N-ethoxycarbonylamino}piperidino]-6,7-dimethoxyquinazoline##STR19## (m) --OCONH(CH₂)₂ CH₃, i.e.4-[4-{n-propylcarbamoyloxy}piperidino]-6,7-dimethoxyquinazoline

(n) --NHSO₂ NH(CH₂)₂ CH₃, i.e.4-[4-{N-(n-propylsulfamoyl)amino}-piperidino]-6,7-dimethoxyquinazoline

(o) --NHSO₂.(3-pyridyl), i.e.4-[4-{3-pyridinesulfonamido}piperidino]-6,7-dimethoxyquinazoline##STR20## and (r) --NHCO(CH₂)₂ CH₃, i.e.4-[4-{butyramido}piperidino]-6,7-dimethoxyquinazoline.

The compounds of the invention can be administered alone but willgenerally be administered in admixture with a pharmaceutical carrierselected with regard to the intended route of administration andstandard pharmaceutical practice. For example they may be administeredorally in the form of tablets containing such excipients as starch orlactose, or in capsules either alone or in admixture with excipients, orin the form of elixirs or suspensions containing flavouring or colouringagents. They may be injected parenterally, for example, intravenously,intramuscularly or subcutaneously. For parenteral administration, theyare best used in the form of a sterile aqueous solution which maycontain other solutes, for example, enough salts or glucose to make thesolution isotonic.

For administration to man in the curative or prophylatic treatment ofcardiac conditions such as congestive heart failure, it is expected thatoral dosages of the most active compounds of the invention will be inthe range from about 20 mg. to 1g. daily, taken in 2 to 4 divided dosesper day, for an average adult patient (70 kg.). Dosages for intravenousadministration would be expected to be within the range 1 to 300 mg. persingle dose as required, for example in the treatment of acute heartfailure. Thus for a typical adult patient, individual tablets orcapsules might contain from about 5 to 500 mg. of active compound, in asuitable pharmaceutically-acceptable vehicle or carrier.

Thus the present invention provides a pharmaceutical compositioncomprising a compound of the formula (I) as defined above together witha pharmaceutically acceptable carrier.

The following examples are provided solely for the purpose ofillustration and are not to be construed as limitations of thisinvention, many variations of which are possible without departing fromthe spirit or scope thereof.

EXAMPLE I ##STR21## 4-Chloro-6,7-dimethoxyquinazoline (45 g),4-(3-n-butylureido)piperidine monhydrochloride (80 g) and triethylamine(140 ml) were refluxed in ethanol (450 ml) for 11/4 hours. The mixturewas then concentrated in vacuo and the resultant solid was stirred inwater which was then basified to pH 11 with 5N NaOH solution. Thesuspension was shaken with chloroform and the organic layer wasseparated, dried (Na₂ CO₃) and evaporated to dryness in vacuo to give ayellow oily solid. Trituration with ether followed by recrystallizationfrom ethanol gave4-(4-[3-n-butylureido]piperidino)-6,7-dimethoxyquinazoline (37 g). Smalltraces of impurities were removed by running a chloroform solution ofthe product down a glass column packed with "Florisil" and eluting with10% isopropanol in chloroform. After evaporation, appropriate fractionswere bulked and recrystallized from ethanol to give a pure product (21g), m.p. 204°-5° C.

Anal. Calcd. for: C₂₀ H₂₉ N₅ O₃ : C, 62.0; H, 7.5; N, 18.1; Found: C,62.1; H, 7.6; N, 18.3

The mono maleate salt was prepared by treating an alcoholic solution ofthe free base with an alcoholic solution of maleic acid. Theprecipitated salt was recrystallized (from EtOH) m.p. 195°-197° C.

The following compounds were prepared, using the method of Example 1,from the appropriate 4-chloroquinazoline derivative and amine, and wereisolated in the form indicated. Both the theoretical and found analysesof the compounds are given, the found analyses being in parenthesis.##STR22##

EXAMPLE 10

Part A

Preparation of 4-[4-(2-pyridylmethyl amino)piperidino]-6,7dimethoxyquinazoline.

1-(6,7-Dimethoxyquinazolin-4-yl)piperid-4-one (2.9g) (which may beprepared as in part A of Example 91, hereinafter), and2-aminomethylpyridine (1.19g) were refluxed together for two hours inbenzene (50 ml.) in a flask fitted with a Dean and Stark trap. Ethanol(50 ml.) was added to the cooled solution followed by the slow additionof sodium borohydride (0.76g) with stirring. On completion of theaddition stirring as continued for two hours followed by the addition ofexcess acetic acid. The mixture was poured into water, basified with 5Nsodium hydroxide and was extracted with chloroform. Evaporation of thechloroform layer gave a yellow oil which solidified on trituration withether. Recrystallization from ethyl acetate gave4-[4-(2-pyridylmethyl-amino)piperidino]-6,7-dimethoxyquinazoline (2 g)m.p. 151°-155° C.

Part b

preparation of4-[4-{3-n-butyl-1-(2-pyridylmethyl)ureido}piperidino]-6,7-dimethoxyquinazoline.##STR23## n-Butyl isocyanate (1 g) was added slowly to a stirredsolution of 4-[4-(2-pyridylmethylamino)piperidino]-6,7-dimethoxyquinazoline, (1.4 g)prepared as in part A above, in dry chloroform, followed by standing atroom temperature for 30 minutes. The solution was evaporated to drynessin vacuo to give a yellow oil which crystallized on trituration withether. Recrystallization from ethyl acetate gave4-[4-{3-n-butyl-1-(2-pyridylmethyl)ureido}piperidino]6,7-dimethoxyquinazoline(1.2 g) as pale yellow crystals, m.p. 162°-4° C.

Anal. Calcd. for C₂₆ H₃₄ N₆ O₃ : C, 65.25; H, 7.2; N, 17.6; Found: C,65.2; H, 7.2; N, 17.4%

EXAMPLE 11

A. preparation of 4-[4-(methylamino)piperidino]-6,7-dimethoxyquinazolineacetate.

1-(6,7-Dimethoxyquinazolin-4-yl)piperid-4-one (14.35 g -- prepared asdescribed in Exaple 91 Part A hereinafter) and ethanolic methylamine(33% w/w; 23.5 g) were stirred together in dry ethanol (150 ml)overnight. Sodium borohydride (2.0 g) was then added slowly under anitrogen atmosphere with cooling. The mixture was then refluxed for 1hour, cooled to room temperature and treated carefully with excessacetic acid. The mixture, after dilution with water and basificationwith 5N NaOH, was extracted with chloroform. After separation, thechloroform phase was dried (MgSO₄) and evaporated to give a crude oilyproduct (10 g) which crystallized on trituration with a mixture of ethylacetate and ether.

Recrystallization from acetonitrile and then ethyl acetate gave pure4-[4-(Methylamino)piperidino]-6,7-dimethoxyquinazoline acetate, m.p.169°-172°.

Anal. Calcd.: C₁₆ H₂₂ N₄ O₂.C₂ H₄ O₂ : C, 59.7; H, 7.2; N, 15.5% Found:C, 59.2; H, 7.5; N, 15.7%

B. preparation of4-[4-(1-methyl-3-n-propyl-ureido)piperidino]-6,7-dimethoxyquinazoline.##STR24## 4-[4-(Methylamino)piperidino]-6,7-dimethoxyquinazoline (1.7 g)was dissolved in chloroform (10 mls.) and treated with n-propylisocyanate (0.5 g). After standing overnight at room temperature themixture was evaporated to dryness. The residue solidified on triturationwith ethyl acetate. Recrystallisation from ethanol gave pure4-[4-{1-methyl-3-n-propyl-ureido}piperidino]-6,7dimethoxyquinazoline(0.4 g) m.p. 209°-11°.

Anal. Calcd for: C₂₀ H₂₉ N₅ O₃ .1/4H₂ O: C, 61.3; H, 7.6; N, 17.9%;Found: C, 61.3; H, 7.6; N, 17.4%

The following compounds were prepared, using the method of Examples 10and 11, from the appropriate 4- piperidino -quinazoline and isocyanateor isothiocyanate, and isolated in the form indicated. In Example 18,sodium cyanate was used. Both the theoretical and found analyses of theproducts are given, the found analyses being in parentheses.

                                      TABLE II                                    __________________________________________________________________________     ##STR25##                                                                                                                        Analysis                                             Position of Y and R                                                                       Salt/Free Base/Hydrate                                                                     (Found in brackets)       Example                                                                            R.sub.1                                                                          R Y                in piperidine nucleus                                                                     m.p.° C                                                                               C  H  N                 __________________________________________________________________________    12   H  H NHCONHCH.sub.3   4-          monomaleate; 205-207°                                                                54.66 5.90 15.18                                                             (54.95 5.76 14.78)        13   H  H NHCSNH(CH.sub.2).sub.3 CH.sub.3                                                                4-          monomaleate; 195-198°                                                                55.47 6.40 13.48                                                             (55.35 6.36 13.10)        14   H  H NHCONH(CH.sub.2).sub.2 CH.sub.3                                                                4-          Free base; 212-214°                                                                  61.10 7.29 18.75                                                             (61.25 7.33 19.22)        15   H  H NHCONHCH.sub.2 CH.sub.3                                                                        4-          Free base; 214-216°                                                                  60.15 7.01 19.49                                                             (59.88 7.07 19.45)        16   H  H NHCONH-Phenyl    4-          Free base; 225-227°                                                                  64.85 6.18 17.19                                                             (64.61 6.32 16.86)        17   H  H                                                                                ##STR26##       4-          Free base; 202-204°                                                                  65.25 7.16 17.56                                                             (65.06 7.20 17.33)        18   H  H NHCONH.sub.2     4-          Free base; 237.5-240°                                                                57.99 6.39 21.13                                                             (57.57 6.43 20.62)        19   H  H NHCONH(3-pyridyl)                                                                              4-          dimaleate 1/2 hydrate;                                                                      53.61 5.12 12.94                                                132-144° C                                                                          (53.31 5.14 12.98)        20   H  H                                                                                ##STR27##       4-          Free base; 167-169°                                                                  65.25 7.16 17.56                                                             (64.04 7.17 17.69)        21   H  H                                                                                ##STR28##       4-          Free base; 196-198°                                                                  67.90 7.39 14.66                                                             (67.55 7.47 14.72)        22   H  H                                                                                ##STR29##       4-          Free base; 175-177°                                                                  64.63 6.94 18.09                                                             (64.57 7.22 18.09)        23   H  H                                                                                ##STR30##       4-          Free base; 140-142°                                                                  62.85 8.35 18.33                                                             (62.95 8.40 18.31)        24   H  H NHCONHCH.sub.2 COOC.sub.2 H.sub.5                                                              4-          Free base; 209-211°                                                                  57.54 6.52 16.78                                                             (57.70 6.56 16.50)        25   H  H                                                                                ##STR31##       4-          Free base; 178-181°                                                                  62.82 7.78 17.44                                                             (62.65 7.79 17.39)        26   H  H                                                                                ##STR32##       4-          Free base; 121-124°                                                                  68.72 8.39 14.57                                                             (68.63 8.07 14.27)        27   H  H                                                                                ##STR33##       4-          Free base; 196- 198°                                                                 62.82 7.78 17.44                                                             (62.51 7.91 17.03)        28   H  H                                                                                ##STR34##       4-          Free base; 151-153°                                                                  64.98 8.41 15.79                                                             (64.58 8.51 15.58)        29   H  H                                                                                ##STR35##       4-          Free base; 232-235°                                                                  63.98 6.71 18.65                                                             (63.87 6.85 18.46         30   H  H                                                                                ##STR36##       4-          Free base; 186-188°                                                                  61.99 7.54 18.08                                                             (61.25 7.59 18.19)        31   H  H                                                                                ##STR37##       4-          Free base; 204-207°                                                                  61.99 7.54 18.08                                                             (61.23 7.63 17.83)        32   H  H                                                                                ##STR38##       4-          Free base; 174-176°                                                                  62.82 7.78 17.44                                                             (63.01 7.28 17.49)        33   H  H                                                                                ##STR39##       4-          Free base; 169-172°                                                                  65.83 7.37 17.06                                                             (65.80 7.38 17.23)        34   H  H                                                                                ##STR40##       4-          Free base; 174-175°                                                                  62.82 7.78 17.44                                                             (63.13 7.75 17.08)        35   H  H                                                                                ##STR41##       4-          Free base; 161-162°                                                                  63.59 8.00 16.86                                                             63.37 8.13 16.60)         36   H  H                                                                                ##STR42##       4-          Free base 1/2 hydrate, 130-133.degr                                           ee.           64.64 7.44 16.76                                                             (64.48 7.44 16.80)        37   H  H                                                                                ##STR43##       4-          Free base; 155-159°                                                                  63.59 8.00 16.85                                                             (63.03 7.89 16.56)        38   H  H                                                                                ##STR44##       4-          Free base; 192-194°                                                                  61.11 7.29 18.75                                                             (61.46 7.29 18.62)        39   H  H                                                                                ##STR45##       4-          Free base; 173-175°                                                                  62.82 7.78 17.44                                                             (63.04 7.95 17.38         40   H  H                                                                                ##STR46##       4-          Free base; 182-184°                                                                  61.99 7.54 18.07                                                             (63.08 7.59 17.99)        41   H  H                                                                                ##STR47##       4-          Free base; 212-220°                                                                  57.58 6.71 18.65                                                             (57.18 6.79 18.70)        42   H  H                                                                                ##STR48##       4-          Free base; 161-165°                                                                  60.41 7.48 16.77                                                             (60.10 7.63 16.81)        43   H  H                                                                                ##STR49##       4-          Free base; 229-231°                                                                  59.53 7.25 17.36                                                             (59.28 7.20 17.58)        __________________________________________________________________________

EXAMPLE 44

Part A

Preparation of 4-[4-amino piperidino]-6,7-dimethoxyquinazoline.

4-Chloro-6,7-dimethoxyquinazoline (0.9 g),4-(trifluoroacetylamino)-piperidine hydrochloride (75% pure, 1.25 g)triethylamine (2.2 ml.) and ethanol (25 ml.) were relfuxed together foraproximately 0.75 hr. The mixture was evaporated in vacuo to drynessfollowed by basification with aqueous 5N sodium hydroxide solution andextraction with chloroform. The chloroform extract was dried andevaporated in vacuo to give, after recrystallisation from ethanol4-(4-trifluoroacetamido piperidino)-6,7-dimethoxyquinazoline (1.5 g)m.p. 217°-220° C.

Anal. Calcd for C₁₇ H₁₉ F₃ N₄ O₃ : C, 50.7; H, 5.3; N, 13.9%; Found: C,50.8; H, 4.75; N, 13.9

4-(4-Trifluoroacetamido piperidino)-6,7-dimethoxyquinazoline (59.5 g)5N- sodium hydroxide solution (250 ml.) and tetrahydrofuran (500 ml.)were refluxed together with stirring for 2 1/2 hours. The T.H.F. layerwas decanted off and concentrated to a small volume followed bytreatment with water and extraction into CHCl₃.

Evaporation of the chloroform gave a yellow oil which on triturationwith ether gave yellow crystals of4-(4-aminopiperidino)-6,7-dimethoxyquinazoline (42 g) m.p. 133°-135° C.

Part B

Preparation of4-[4-(ethoxycarbonylamino)piperidino]-6,7-dimethoxyquinazoline.##STR50## 4-[4-Aminopiperidino]-6,7-dimethoxyquinazoline prepared as inpart A, (1.4 g), ethyl chloroformate (0.65 g) and triethylamine (1.1ml.) were stirred together in dry chloroform (30 ml.) at roomtemperature for 1 hour. After concentration in vacuo the residue wassuspended in water, basified with 5N sodium hydroxide solution andextracted with chloroform. The extract was dried (MgSO₄) and evaporatedin vacuo to give the product as a pale yellow oily solid. The solid wasre-dissolved in ethylacetate and converted to the tartrate salt by theaddition of an ethanolic solution of tartaric acid. The tartrate wasre-dissolved in hot ethanol and a small amount of impure material wasallowed to crystallize out. The filtrate was taken, evaporated todryness, rebasified in dilute aqueous sodium hydroxide solution andextracted with chloroform. Evaporation of the dried chloroform extractand recrystallization of the residue from ethylacetate gave4-[4-(ethoxycarbonylamino)piperidino]-6,7-dimethoxyquinazoline (300 mg)m.p. 179°-181° C.

Anal. Calcd. for C₁₈ H₂₄ N₄ O₄ : C, 60.0; H, 6.7; N, 15.6; Found: C,60.1; H, 6.8; N, 15.1%

The following compounds were prepared, using the method of Example 44,from the appropriate 4-(4-aminopiperidino)- or 4-(4-loweralkylaminopiperidino)-6,7-dimethoxyquinazoline, and the appropriatechloroformate (Examples 55 to 59 and 63), acyl chloride (Examples 46, 50and 52), sulfonyl chloride (Examples 48, 49, 54 and 68), sulfamylchloride Examples 47, 53, 62 and 64), carbamyl chloride (Examples 45 and51), anhydride (Examples 65 and 67) and pyrocarbonate (Examples 60, 61and 66 used (EtO.CO)₂ O). The products were isolated in the formindicated. The theoretical and found analyses of the products are given,the found analyses being in parentheses.

    __________________________________________________________________________     ##STR51##                                                                                                                       Analysis %                                          Position of Y in                                                                        Salt/Free Base/Hydrate                                                                        (Found in brackets)        Example                                                                            R.sub.1                                                                         R      Y          piperidine nucleus                                                                      m.p.° C  C  H  N                    __________________________________________________________________________    45   H H NHCON(CH.sub.3).sub.2                                                                         4-        Free base; 178-183° C                                                                   60.15 7.01 19.48                                                             (59.63 7.13 18.95)         46   H H NHCO(3-pyridyl) 4-        Free base; 225-227° C                                                                   64.11 5.89 17.80                                                             (63.79 6.07 17.45)         47   H H NHSO.sub.2 N(CH.sub.3).sub.2                                                                  4-        Free base; 182-184° C                                                                   51.64 6.37 17.71                                                             (51.97 6.43 17.61)         48   H H NHSO.sub.2 CH.sub.3                                                                           4-        monohydrochloride monohydrate;                                                                  45.66 5.98 13.31                                            215-220° C                                                                             (45.30 5.78 13.38)         49   H H NHSO.sub.2 (3-pyridyl)                                                                         4-       Free base; 222-225° C                                                                   55.93 5.40 16.31                                                             (56.19 5.23 16.61)         50   H H NHCO(CH.sub.2).sub.3 CH.sub.3                                                                 4-        monohydrochloride; 212-215°                                                             58.74 7.15 13.70                                                             (58.51 7.17 13.09)         51   H H NHCON(C.sub.2 H.sub.5).sub.2                                                                  4-        monohydrochloride 1/2-                                                                         55.48 7.22 16.18                                             hydrate; 215-218° C                                                                    (55.78 7.03 15.88)         52   H H NHCOCH.sub.2 CH.sub.2 CH.sub.3                                                                4-        Free base; 157-159° C                                                                   63.67 7.31 15.63                                                             (63.99 7.55 15.24)         53   H H NHSO.sub.2 NH(CH.sub.2).sub.2 CH.sub.3                                                        4-        Monohydrochloride 1/2-                                                                         47.51 6.42 15.39                                             hydrate; 222-224° C                                                                    (47.47 6.55 15.49)         54   H H                                                                                ##STR52##      4-        Mono p-toluene sulphonate; 241-244.degr                                       ee. C            54.78 5.36 10.65                                                             (54.55 5.46 10.57)         55   H H                                                                                ##STR53##      4-        Mono-maleate; 169-173°                                                                  59.54 5.38 10.68                                                             (59.64 5.47 10.31)         56   H H NHCOOCH.sub.3   4-        Free base; 162-166° C                                                                   58.95 6.40 16.17                                                             (58.67 6.35 15.87)         57   H H NHCOOCH.sub.2 CH(CH.sub.3).sub.2                                                              4-        Mono-maleate; 173-175° C                                                                57.13 6.39 11.10                                                             (56.88 6.18 10.71)         58   H H                                                                                ##STR54##      4-        Oxalate; 198-203° C                                                                     58.59 5.51 10.93                                                             (58.19 5.57 11.32)         59   H H NHCOO(CH.sub.2).sub.2 CH.sub.3                                                                4-        Oxalate 1/2-hydrate,                                                                           53.27 6.17 11.83                                             190-196° C                                                                             (53.06 5.92 11.96)         60   H H                                                                                ##STR55##      4-        Free base; 145-147° C                                                                   60.95 7.00 14.96                                                             (60.56 7.00 14.58)         61   H H                                                                                ##STR56##      4-        Free base; 149-152° C                                                                   61.84 7.27 14.42                                                             (61.66 7.36 13.88)         62   H H                                                                                ##STR57##      4-        Free base; 174-179° C                                                                   53.88 6.90 16.54                                                             (54.27 6.99 16.54)         63   H H                                                                                ##STR58##      4-        Free base; 159-162° C                                                                   62.67 7.51 13.92                                                             (62.47 7.54 13.61)         64   H H                                                                                ##STR59##      4-        monohydrochloride monohydrate,                                                174-189° C                                                                              48.81 6.98 14.23                                                             (48.90 6.72 14.02)         65   H H                                                                                ##STR60##      4-        Free base; 177-180° C                                                                   62.77 7.02 16.27                                                             (62.36 7.09 16.03)         66   H H                                                                                ##STR61##      4-        Free base; 185-187° C                                                                   59.39 6.98 13.85                                                             (58.91 6.99 13.94)         67   H H                                                                                ##STR62##      4-        Free base; 155-158° C                                                                   64.49 7.58 15.04                                                             (64.44 7.65 14.73)         68   H H                                                                                ##STR63##      4-        Free base; 183-187° C                                                                   56.87 5.68 15.79                                                             (57.27 5.61                __________________________________________________________________________                                                       15.90)                 

EXAMPLE 69 ##STR64## 4-[4-Hydroxy piperidino]-6,7-dimethoxyquinazoline(2.9 g) and 3-pyridyl isocyanate (1.3 g) in 40 ml. of dry dioxane wereheated together at 150° C in a stainless steel bomb for 24 hours. Thecooled mixture was concentrated in vacuo to give a brown sticky solidwhich was triturated with ether and filtered. The insoluble residue wascrystallized from acetonitrile to give4-[4-(3-pyridylcarbamoyloxy)piperidino]-6,7-dimethoxyquinazoline (1.4 g)m.p. 180°-183° C.

Anal. Calcd. for C₂₁ H₂₃ N₅ O₄ : C, 61.3; H, 5.7; N, 17.1; Found: C,61.3; H, 5.5; N, 17.5&

The following compounds were prepared, using the method of Example 69,from the appropriate 4-(4-hydroxypiperidino)quinazoline [or4-(3-hydroxypyrrolidin-1-yl)- 6,7-dimethoxyquinazoline in the case ofExample 78] and the appropriate isocyanate (or sodium cyanate in the caeof Example 76), and the products were isolated in the form indicated.The theoretical and found analyses of the products are given, the foundanalyses being in parentheses.

                                      TABLE IV                                    __________________________________________________________________________     ##STR65##                                                                                                               Analysis                                                Position of Y in                                                                        Salt/Free Base/Hydrate                                                                    (Found in brackets)                Example                                                                            R.sub.1                                                                         R  Y          piperidine nucleus                                                                      m.p. ° C                                                                           C   H   N                          __________________________________________________________________________    70   H H  OCONHCH.sub.3                                                                            4-        Free base; 195-198° C                                                              58.95                                                                             6.40                                                                              16.17                                                                 (59.05                                                                            6.47                                                                              16.19)                     71   H H  OCONH(CH.sub.2).sub.3 CH.sub.3                                                           4-        Free base; 127-129° C                                                              61.84                                                                             7.27                                                                              14.42                                                                 (62.09                                                                            7.30                                                                              14.08)                     72   H H  OCONH(CH.sub.2).sub.2 CH.sub.3                                                           4-        Free base; 164-167° C                                                              60.95                                                                             7.00                                                                              14.96                                                                 (61.00                                                                            6.98                                                                              15.29)                     73   H CH.sub.3                                                                         OCONH(CH.sub.2).sub.2 CH.sub.3                                                           4-        Free base; 161-165° C                                                              61.84                                                                             7.27                                                                              14.42                                                                 (61.46                                                                            7.19                                                                              14.07)                     74   H H  OCONHCH.sub.2 CH.sub.3                                                                   4-        Free base; 168-170° C                                                              59.98                                                                             6.71                                                                              15.55                                                                 (59.98                                                                            6.76                                                                              15.45)                     75   H CH.sub.3                                                                         OCONHCH.sub.3                                                                            4-        Free base; 199-207° C                                                              59.98                                                                             6.71                                                                              15.55                                                                 (59.56                                                                            6.76                                                                              15.20)                     76   H H  OCONH.sub.2                                                                              4-        monohydrochloride,                                                                        52.11                                                                             5.74                                                                              15.19                                                     232-235° C                                                                         (51.90                                                                            5.78                                                                              15.00)                     __________________________________________________________________________     ##STR66##                                                                    77   H H  OCONHCH.sub.2 CH.sub.3                                                                   4-        Free base; 286-288° C                                                              60.95                                                                             7.00                                                                              14.96                                                                 (60.71                                                                            7.12                                                                              14.71)                     __________________________________________________________________________     ##STR67##                                                                                                               Analysis %                                              Position of Y in                                                                        Salt/Free Base/Hydrate                                                                    (Found in brackets)                Example                                                                            R.sub.1                                                                         R  Y          pyrrolidine nucleus                                                                     m.p.° C                                                                            C   H   N                          __________________________________________________________________________    78   H H  OCONH(CH.sub.2).sub.2 CH.sub.3                                                           3-        Free base; 186-189° C                                                              60.00                                                                             6.71                                                                              15.55                                                                 (59.97                                                                            6.94                                                                              15.66)                     __________________________________________________________________________     ##STR68##                                                                     ##STR69##                                                                     ##STR70##                                                                        4-[4-Amino piperidino]-6,7-dimethoxyquinazoline (which may be             prepared via the route of part A of Example 44) (5.8 g), triethyl amine       (14 ml.) and chloroform (100 ml.) were added slowly to a solution of          phosgene in toluene (48 ml. of 12 1/2 w/v). The mixture was stirred at        room temperature during the addition and then allowed to stand overnight.     Amino pentane (5.23 g) was then added slowly followed by standing for a       further 24 hours. 2N hydrochloric acid (200 ml.) was added and the            organic phase was collected and evaporated to dryness in vacuo to give an     oil. The oil was dissolved in water, basified with 5N NaOH and extracted      with chloroform. The extract was dried and evaporated in vacuo to give an     oil which solidified on standing under petroleum ether. Recrystallization     from acetonitrile gave 4-[4-(3-n-pentylureido)piperidino]-6,7-dimethoxyqui

Anal. Calcd. for C₂₁ H₃₁ N₅ O₃ : C, 62.8; H, 7.8; N, 17.4; Found: C,62.4; H, 8.0; N, 17.8%

The following compounds were made, using the method of Example 79, from4-(4-aminopiperidino)-6,7-dimethoxyquinazoline, phosgene, and theappropriate amine. The compounds were isolated in the form indicated,and the theoretical and found analyses are given, the found analysesbeing in brackets.

                                      TABLE V                                     __________________________________________________________________________     ##STR71##                                                                                                                       Analysis %                                          Position of Y in                                                                         Salt/Free Base/Hydrate                                                                       (Found in brackets)        Example                                                                            R.sub.1                                                                         R  Y              piperidine nucleus                                                                          m.p.° C                                                                            C   H   N                  __________________________________________________________________________    80   H H  NHCONH . CH.sub.2 CH(CH.sub.3).sub.2                                                         4-         monotartrate; 122-135°                                                                53.62                                                                             6.56                                                                              13.03                                                                 (53.39                                                                            6.68                                                                              13.31)             81   H H                                                                                 ##STR72##     4-         Dihydrochloride; 196-201°                                                              53.39 (53.87                                                                     6.61 6.48                                                                         14.82 15.54)       82   H H  NHCONH(CH.sub.2).sub.4 OH                                                                    4-         Free base; 131-145° C                                                                 59.54                                                                             7.24                                                                              17.36                                                                 (58.96                                                                            7.04                                                                              16.97)             83   H H  NHCONH(CH.sub.2).sub.2 (2-                                                                   4-         Free base; 199-201° C                                                                 63.29                                                                             6.47                                                                              19.25                        pyridyl)                                 (63.26                                                                            6.37                                                                              18.96)             84   H H  NHCONHCH.sub.2 CHCH.sub.2                                                                    4-         Free base; 211-214° C                                                                 61.44                                                                             6.78                                                                              18.85                                                                 (61.13                                                                            6.81                                                                              18.85)             85   H H                                                                                 ##STR73##     4-         monohydrate; 187-190° C                                                               58.90                                                                             6.50                                                                              18.07                                                                 (59.55                                                                            6.30                                                                              17.91)             __________________________________________________________________________

EXAMPLE 86 ##STR74## 4-(4-Aminopiperidino)-6,7-dimethoxyquinazoline(which may be prepared via the route of part A of Example 44) (2.9 g)and N-[3-(-t-butoxycarbonylamino)propionyloxy]succinimide (2.9 g) werestirred for 2 hours at room temperature in dry chloroform (40 ml.). Themixture was filtered and the filtrate was treated with aqueous sodiumcarbonate solution (10% w/v) followed by separation of the organic phasewhich was dried (Na₂ CO₃) and evaporated to dryness in vacuo. Thet-butoxycarbonyl group was then removed by dissolving the residue inmethanol (40 ml.) followed by refluxing for 4 hours with the addition of2N aqueous HCl (12 ml.). The mixture was evaporated to dryness in vacuoand the residual hydrochloride was rebasified (5N NaOH) and extractedinto chloroform. The concentrated chloroform solution was passed down acolumn packed with "Florisil"(in chloroform) followed by elution withchloroform-methanol. Appropriate fractions were bulked and evaporated invacuo to give crude 4-(4-[β-aminopropionamido]piperidino)6,7-dimethoxyquinazoline which was dissolved in ethanol an converted tothe dimaleate salt by treatment with a solution of maleic acid inispropanol. Recrystallization from acetonitrile gave the pure dimaleate(500 mg.) m.p. 166°-170° C.

Anal. Calcd. for C₁₈ H₂₅ N₅ O₃ .2C₄ H₄ O₄ : C, 52.8; H, 5.6; N, 11.8;Found: C, 51.9; H, 5.6; N, 11.7%

EXAMPLE 87

Using the method of Example 86, but starting from4-[4-aminopiperidino]-6,7-dimethoxyquinazoline and N-[2-(t-butoxycarbonylamino)isovaleryloxy]succinimide, and using hydrochloric acidinstead of maleic acid in the penultimate step,4-(4-[α-amino-iso-valeramido]piperidino-6,7-dimethoxyquinazolinedihydrochloride dihydrate was isolated, m.p. 218°-222° C.

Anal. Calcd. for C₂₀ H₂₉ N₅ O₃ : C, 48.38; H, 7.11; N, 14.11%; Found: C,49.23; H, 6.86; N, 13.78%

EXAMPLE 88

Using the method of Example 86, starting fromN-(α-methoxyacetyloxy)-succinimide and4-(4-amino-piperidino)-6,7-dimethoxyquinazoline,4-(4-(α-methoxyacetamido)piperidino]-6,7-dimethoxyquinazoline wasprepared, m.p. 133°-135° C.

Anal. Calcd. for C₁₈ H₂₄ N₄ O₄ : C, 59.98; 6.71; N, 15.55%; Found: C,59.77; H, 6.82; N, 15.15%

EXAMPLE 89 ##STR75##4-[4-Ethoxycarbonylmethyl)piperidino]-6,7-dimethoxyquinazoline (whichmay be prepared as in Example 5) (5 g) and n-butylamine (10 ml) wereheated together at about 78° C for 22 hours. The mixture was cooled,basified and extracted with chloroform. The extract was dried andevaporated to dryness in vacuo to give an oil which on dissolution inether crystallized as a white solid. Recrystallization from ethylacetate gave4-[4-(n-butylcarbamoylmethyl)piperidino]-6,7-dimethoxyquinazoline (710mg) m.p. 142°-4° C.

Anal. Calcd. for C₂₁ H₃₀ N₄ O₃ : C, 65.3; H, 7.8; N, 14.5; Found: C,64.9; H, 8.01; N, 14.25%

EXAMPLE 90

Part A

Preparation of4-(4-[α-bromoacetamido]piperidino)-6,7-dimethoxyquinazoline.

4-(4-Aminopiperidino)-6,7-dimethoxyquinazoline (2.9 g) (which may beprepared via the route of Example 44 part A), and triethylamine (1.5 g)in dry chloroform (20 ml.) were treated wih α-bromoacetyl bromide (2.3gm) to obtain a mixture containing4-(4-[α-bromoacetamido]piperidino)-6,7-dimethoxyquinazoline.

Part B

Preparation of4-[4-(α-piperidinoacetamido)piperidino]-6,7-dimethoxyquinazolineditartrate. ##STR76##

The mixture prepared in part A was stirred for 30 minutes at roomtemperature and then piperidine (1.0 gm) was added. After stirring for 3hours at room temperature the mixture was treated with sodium carbonatesolution and the chloroform layer was separated, washed, dried andevaporated to dryness in vacuo to give an oil. The oil was dissolved inisopropanol and converted to the ditartrate by reaction with tartaricacid. Recrystallization from ethanol gave 4-[4-(α-piperidinoacetamido)piperidino]-6,7-dimethoxyquinazoline ditartrate (1.35 g) m.p.138°-141° C.

Anal. Calcd. C₂₂ H₃₁ N₅ O₃.2C₄ H₆ O₆ : C, 50.5; H, 6.1; N, 9.8; Found:C, 50.9; H, 6.3; N, 9.9%

EXAMPLE 91

Part A

Preparation of 4-(4-oxopiperidino)-6,7-dimethoxyquinazoline.

4-Chloro-6,7-dimethoxyquinazoline (30 g), 4-piperidone ethylene ketalhydrochloride (25 g), triethylamine (35 g) and ethanol (250 ml.) wererefluxed together for 3 hours. Aqueous sodium carbonate was addedfollowed by extraction with chloroform after which the chloroformextract was dried and evaporated in vacuo to give an oil. The oil wasredissolved in aqueous hydrochloric acid (1.5N, 200 ml.) and refluxedfor 2 hours followed by cooling, basification (Na₂ CO₃ 10% sol_(n)) andextraction into chlororform. Evaporation of the dried chloroform extractgave 4-(4-oxo-piperidino)-6,7-dimethoxyquinazoline (37.6 g) m.p. 176°-8°C.

Part B

Preparation of4-[4-acetonyl-1,2,3,6-tetrahydropyrid-1-yl]-6,7-dimethoxyquinazolinemonomaleate. ##STR77##

Diethyl acetonylphosphonate in dry dimethoxy ethane (D.M.E.) (50 ml.)was added slowly to a stirred suspension of sodium hydride (1 g, 80% oildispersed) in D.M.E. (50 ml.) followed by stirring at room temperaturefor 30 minutes. 4-(4-oxopiperidino-6,7-dimethoxyquinazoline prepared inpart A 8.8 g) in D.M. E. (100 ml.) was added rapidly followed by heatingat 80° C for 1 hour. The solution was poured into ice-water andextracted with chloroform. The organic layer was separated, dried anconcentrated in vacuo to give an oil which was dissolved in toluene andconverted to the maleate by treatment with ethereal maleic acid.Recrystallization from ethanol gave4-[4-acetonyl-1,2,3,6-tetrahydro-pyrid-1-yl]-6,7-dimethoxyquinazolinemonomaleate, m.p. 179°-181° C.

Anal. Calcd. for C₁₇ H₂₁ N₃ O₃.C₄ H₄ O₄ : C, 59.6; H, 5.7; N, 9.5;Found: C, 58.7; H, 5.7; N, 9.3%

The following compound was prepared, using the method of Example 91,from 4-(4-oxo piperidino)-6,7-dimethoxyquinazoline and diethylethoxycarbonylmethylphosphonate, the product being isolated in the formindicated. The theoretical and found analysis of the compound are given,the found analysis being in parentheses.

                                      TABLE VI                                    __________________________________________________________________________     ##STR78##                                                                                                Analysis                                                                      (Found in brackets)                               Example                                                                            R.sub.1                                                                         Y        Salt/Free Base m.p.°  C                                                            CHN                                               __________________________________________________________________________    92   H CH.sub.2 COOC.sub.2 H.sub.5                                                            Free base; 133-135° C                                                              63.85 6.48 11.76                                                              (63.50 6.65 11.47                                 __________________________________________________________________________

EXAMPLE 93##STR79##4-(4-[Carboxymethyl]-1,2,3,6-tetrahydropyrid-1-yl)-6,7-dimethoxyquinazolinehydrochloride (0.92 g) (prepared by hydrolysis of the ester of Example92) in dry chloroform (20 ml.) containing triethylamine (0.3 g) wasstirred until complete solution occurred. Dicyclohexylcarbodiimide (0.63g) and N-hydroxy-succinimide (0.35 g) were added followed by standingovernight during which time a white solid precipitated. n-Butylamine(0.22 g) was added and the mixture again left to stand (5 hours) afterwhich the solution was filtered, washed with water and the organic phaseevaporated to dryness in vacuo. The residue was triturated withacetonitrile, filtered and the filtrate was treated with ethereal HCluntil acid. The precipitated hydrochloride of4-[4-(n-butylcarbamoylmethyl)-1,2,3,6-tetrahydropyrid-1-yl]-6,7-dimethoxyquinazolinewas recrystallized from ethanol (yielded 340 mg) m.p. 196° (as ahemihydrate).

Anal. Calcd. for C₂₁ H₂₈ N₄ O₃.HCl.1/2H₂ 0: C, 58.65; H, 7.0; N, 13.0;Found: C, 58.2; H, 6.6; N, 12.9%

EXAMPLE 94

The following is an Example of a typical parenteral formulation,intended for intravenous injection, in which the active ingredient isthe compound of Example 1.

    ______________________________________                                                       mg/ml                                                          Active ingredient                                                                              5.0                                                          Sodium chloride  8.5                                                          Hydrochloric acid                                                                              Sufficient for pH                                                             adjustment                                                   Water            Sufficient to bring                                                           correct volume                                               ______________________________________                                    

The active ingredient and sodium chloride are dissolved in a little ofthe hydrochloric acid, and more of the latter is added until the pH ofthe solution is within the limits 3.75± 0.25, and the volume as nearlyapproaches the desired final volume as possible. Water is then added tobring the volume to the appropriate volume for the active ingredient andthe salt to be present at the desired concentrations.

What is claimed is:
 1. A compound selected from the group consisting of##STR80## and the pharmaceutically acceptable acid addition saltsthereof, wherein R₁ is selected from the group consisting of hydrogenand alkyl having from one to three carbon atoms;R₂ is alkoxy having fromone to two carbon atoms; X is selected from the group consisting of--CH=CH--, and alkylene having from one to two carbon atoms; and Y is asubstituent at the 3- or 4-position of ring C selected from the groupconsisting of --Z₁ COR₃, --N(R₄)SO₂ R₅, --Z₂ CONR₆ R₇ and Z₂ CSNR₆ R₇wherein Z₁ is selected from the group consisting of --CH₂ -- and--N(R₄)--; R₃ is selected from the group consisting of alkyl having fromone to four carbon atoms, alkoxy having from one to four carbon atoms,benzyloxy, phenoxy, ethoxy-carbonylmethyl and pyridyl; R₅ is selectedfrom the group consisting of alkyl having from one to four carbon,pyridyl and --NR₆ R₇ ; Z₂ is selected from the group consisting of--O--, --CH₂ -- and --N(R₄) -- wherein R₄ is selected from the group ofhydrogen, pyridyl, phenyl, alkyl having from one to four carbon atomsand substituted said alkyl wherein said substituent is selected from thegroup consisting of amino, dimethylamino, hydroxy, pyridyl and phenyl;and R₆ and R₇ when considered separately are each selected from thegroup consisting of hydrogen, alkyl having one to four carbon atoms andR₆ and R₇ when considered together with the nitrogen to which they areattached form a piperidine ring, with the proviso that when X is--CH=CH-- or --CH₂ CH=CH-- Y is selected from the group consisting of--CH₂ COR₃, --CH₂ CONR₆ R₇ and --CH₂ CSNR₆ R₇.
 2. A compound of claim 1where R₁ is hydrogen, R₂ is methoxy, X is --CH₂ CH₂ -- and Y is asubstituent at the 4-position.
 3. A compound of claim 2 wherein Y is Z₁COR₃ wherein Z₁ is --N(R₄)-- wherein R₄ is selected from the groupconsisting of hydrogen and alkyl having from one to four carbon atoms,and R₃ is selected from the group consisting of alkyl having from one tofour carbon atoms and alkoxy having from one to four carbon atoms. 4.The compound of claim 3 wherein Y is --NHCO₂ CH₂ CH₃.
 5. The compound ofclaim 3 wherein Y is --N(CH₃)CO₂ CH₂ CH₃.
 6. The compound of claim 3wherein Y is --NHCO₂ CH₂ CH(CH₃)₂.
 7. The compound of claim 3 wherein Yis --NHCO₂ (CH₂)₂ CH₃.
 8. The compound of claim 3 wherein Y is --N(CH₂CH₃)CO₂ CH₂ CH₃.
 9. The compound of claim 3 wherein Y is--N(CH₃)CO(CH₂)₂ CH₃.
 10. The compound of claim 3 wherein Y is--NHCO(CH₂)₂ CH₃.
 11. A compound of claim 2 wherein Y is --N(R₄)SO₂ R₅wherein R₄ is selected from the group consisting of hydrogen and alkylhaving from one to four carbon atoms, and R₅ is selected from the groupconsisting of pyridyl and --NR₆ R₇ wherein R₆ and R₇ when consideredseparately are each selected from the group consisting of hydrogen andalkyl having from one to four carbon atoms.
 12. The compound of claim 11wherein Y is --N(CH₃)SO₂ NH(CH₂)₂ CH₃.
 13. The compound of claim 11wherein Y is --NHSO₂ NH(CH₂)₂ CH₃.
 14. The compound of claim 11 whereinY is --NHSO₂ --(3-pyridyl).
 15. The compound of claim 11 wherein Y is--N(CH₃ SO₂ --(3-pyridyl).
 16. A compound of claim 2 wherein Y is Z₂CONR₆ R₇ wherein Z₂ is selected from the group consisting of --O-- and--N(R₄)-- and R₆ and R₇ when considered separately are each selectedfrom the group consisting of hydrogen and alkyl having from one to fourcarbon atoms, and R⁴ is selected from the group consisting of hydrogen,alkyl of one to four carbon atoms and pyridyl-substituted alkyl.
 17. Thecompound of claim 16 wherein Y is --N(CH₂ CH₂ --[ 4-pyridyl])CONH--(CH₂)₃ CH₃.
 18. The compound of claim 16 wherein Y is --N([CH₂ ]₃CH₃)CONHCH₃.
 19. The compound of claim 16 wherein Y is --N([CH₂ ]₃CH₃)CONH(CH₂)₃ CH₃.
 20. The compound of claim 16 wherein Y is--O--CONHCH₂ CH₃.
 21. The compound of claim 16 wherein Y is--O--CONH(CH₂)₂ CH₃.
 22. The compound of claim 16 wherein Y is--NHCONH(CH₂)₃ CH₃.
 23. The compound of claim 16 wherein Y is--N(CH₃)CONH(CH₂)₂ CH₃.
 24. A method of stimulating the heart of ananimal which comprises administering to said animal a cardiacstimulating amount of a compound selected from the group of claim 1.